Steroidal compounds and methods for obtaining the same



Patented Oct. 8, 1946 UNITED STATES PATENT OFFICE STEROIDAL COMPOUNDS AND METHODS FOR OBTAINING THE SAME Romeo B. Wagner, State College, Pa., assignor to Parke, Davis & Company, Detroit, Mich., a corporation of Michigan N Drawing. Application May 15, 1944, Serial No. 535,748

4 Claims. (Cl. 260-2395) where Y2 and Y3 represent OH H and groups hydrolyzable to on H such as various species of Yucca, by chemical and a physical methods, a new and valuable steroidal compound is obtained which has been named Yuccagenin and has the following structural formula:

ebe

Yuccagenin (011E204) Yuccagenin may also be converted into its diacylates, of which the 'diacetate has the following formula: V

on, CHz-CH: CH; CH: &

H-c (DH-CH1 0'-cH,

AcO

H V Q Ac'O Yuccagenin diacetate (Galli m) These new compounds are useful as intermediates for preparation of physiologically active compounds, such as sex hormones. In general, I first treat the plant source by solvent extraction and hydrolytic procedures combined with fractional crystallizations. The following examples show how to get the new products.

Example 1 4 kilograms of broken up caudex and roots of Yucca elata Engelm. collected near Tucson, Arizona, in the month of December are extracted with hot water or a lower aliphatic alcohol such as h ethyl alcohol and then the solvent is evaporated to leave a, syrupy residue. The saponin-containing residue is then hydrolyzed, for example by refluxing it a few hours with 2 N ethanolic hydrochloric acid, cooling and filtering. The filtrate is diluted with several volumes of diethyl ether and the solution washed successively with water, 5% sodium hydroxide solution and water. Any fatty esters in the residue can be hydrolyzed by refluxing it with a few volumes of 10% alcoholic KOH for about /2 hour. The cooled mixture from the alkaline hydrolysis is extracted with ether and the ethereal solution washed with water and then evaporated to give a, sapogenin fraction which is dissolved in acetone, the solution treated with active charcoal and filtered.

Solvent is then evaporated away.

The acetone filtrate is concentrated and cooled to give a tan solid weighing 8.5 grams and melting at 172-174" C. After two crystallizations from ether, it melts at 185 to 186 C. Two more crystallization from methanol raise the melting point to 19l-192 C. Two final crystallizations from ether give plates, M. P. and mixed M. P. with sarsasapogenin, 199200; wt. is 0.5 g. This sarsasapogenin product can be refluxed with acetic anhydride and the mixture cooled and filtered to give an acetate identical with sarsasapogenin acetate, M. P. and mixed M. P. 128-130 C.

All of the mother liquors from the crystallization of sarsasapogenin are combined and evaporated. The residue is treated with 10% alcoholic KOH for30 minutes. Th reactionmixture is cooled and extracted with ether. The ethereal solution, after washing with water, is concentrated to 50 cc. After standing overnight at 0 0.,

crystals separate out. These areseparated, taken up in ether and recrystallized therefrom toLgiVe a product of M. P. 220-235 C. This product is acetylated with boiling acetic acidranhydride' for 30 minutes, excess anhydride separated from the acetylated product and the latter taken up in and anol it occurs as white plates of M. P. 250-252 C. This is a form polymorphic with thecother form melting at 244-246 C.

'Example 2 iXl iZl xIQfiQUY de lon'ze wa c ti d solution, of i bromine.

. mn; alcoholic solution-of yucca enin when added to a 2%..alcoholicesolution. of digitonin. forms a floc'culent-precipitate. Catalytic-hydrogenation of yuccagenin diacetate (Adams catalyst H2 and PtOz) in ether containingseveral drops of acetic acid followed by hydrolysis "of the reduced ace- :tate andextraction' With'and crystallization from ether-gives 'gitogening M. P.-and mixed M.-'P. 268-272" C.

Anal: Calcd'forgitogenimCmHnOr: C,-75.0%; H,l,l0.3%. Found: C, 74'.7;"H,'-10:0%.

This reduction shows that" yuccagenin differs from gitogenin' in posses'singa double'bond. 'The loca'tion ofthe double bond is'establi'shed'by 13+C. Yuccage'nin 145B; .Gitogenin' the formation'of 'chlorogenonic acid ('17A)-from 75 potassium iodide in ethanol.

yuccagenin by a method somewhat like that employed for diosgenin, Marker, Jones and Turner, J. Am. Chem. Soc, 62, 2537 (1940), and cholesterol, Criegee, Ber., 65, 1720 (1933), Pichard and Yates, J. Chem. Soc., 93, 1678 (1908), Westphalen, Ber., 48, 1064 (1915), Windaus, Ben, 39, 2249 (1906), Windaus, Ben, 40, 257 (1907). The yuccagenin conversion is illustrated by the route, 13-C15-B16A17-A. The reaction of yuccagenin (IS-C) with hydrogen peroxide in acetic acid forms the 2, 3, 5,6-tetrol (15-3). The latter with boiling acetic anhydride forms a triacetate. This might be expected if the double bond is at 5-6 since the 5-hydroxyl is tertiary and does not react. By analogy, diosgenin upon like treatment=forms the"3;5,6-triol whichmakes a.

diacetate, Tsukamoto, Ueno, Ohta andTschesche.

Ben, 57, 283 (1937). Oxidation of the tetrol i (15-B) with cold chromic acid gives a monobasic acid (16-'A) having the composition 027113807. "The 3-carboxyl group has probably lactonized with the. 5 hydroxyl since the usual dehydration treatment employed for a 3,6-diketo-5-ol gives unchanged material.

Treatment of this product with zinc in acetic acid, however, gives a ketodiacid identical with chlorogenonic .acid- (17-,-A). The identity is further established by a direct comparison of the dimethyl esters. The conditions of the zinc-acetic acid reaction used here follow those employed for .thereduction of the enedione obtained from diosgenin to chlorogenone.

By using the 5-6 double bond to good advantage, yuccagenin canbe-convertedto 7-.ketogitogenie "acid (30+E). ,This .series. ofreaction, viz. .1fie-0+25 D 26-D+127-D: 28-E+229- E 3O-E, follows essentially1thatv used'zfor :converting diosgenin to 7-ketotigogenin acetate. Thus, yuccagenin diacetatewreacts with twicethe molecular .quantity of bromine in acetic'acid to give 5,6;23-

tribromoyuccagenin diacetate (25D). The 5,6- double bond is regeneratedby treatment with In this manner, a bromine atom has been placed in the side-chain, thus protecting the latter from toogreat oxidation in the next step. ;By using conditions developed by Windaus, ,Lettre-and Schwenck, Ann., 520, 98 (1935), for the preparation of 'Z-ketocompounds, 23 bromoyuccagenin -diacetate (26-D) can be converted to 7-keto-23-,bromoyuccagenin diacetate (27-D). The double-bond in the latter (27-D) is selectively hydrogenated using palladium-barium sulphate catalyst, resulting in the formation of 7-keto-23-bromogitogenin diacetate (28-E). .Debromination of this substance (28-E) with zinc in aceticacid- -D. 5,6,23-tribromo yuccagenin diacetate ever, one can use any of the known agents for converting the alcoholic hydroxyls at C-2 and 26-D. 23-bromoyuccagenin diacetate Chromicl acid HO 0 GAG/K Hydrolysis;

A 0 O Chromic acid H 0 0 C O 29-E. 7-ketogitogenin diacetate 30-E. 7-ketogitogenlc acid leaves the carbonyl group intact to give 'I-ketogitogenin diacetate (29-E). The presence of the carbonyl group in 29-E has been ascertained by its formation of a 2,4-dinitrophenylhydrazone. Its removal by the WolfI-Kishner method gives gitogenin, proving that the basic structure of 29-E has not been altered. Hydrolysis of the keto-diacetate (29-E) followed by mild chromic acid oxidation gives 7-ketogitogenic acid (30-E). This compound is entirely different from digitogenic acid and digitoic acid. The non-identity is further established by their dimethyl esters.

Yuccagenin can be converted to a pseudosapogenin which is reconverted to the original sapogenin when treated with acid. The pseudocompound after oxidation and subsequent hydrolysis is converted to 5,l6-pregnadien-2,3(,B)- diol-ZO-one. Other than having a 0-2 hydroxyl group, this pregnene compound is identical with 5,16-pregnadien-3([i) -ol-20-one. The absorption curves bear out this close relationship. Selective hydrogenation of the l6-double bond using 3% palladium-barium sulphate catalyst gives 5- pregnen-2,3(fl)-diol-20-one. Additional support for the structure of pseudoyuccagenin triacetate is given by its conversion to the triacetate of dihydro-pseudo-gitogenin.

Catalytic hydrogenation of yuccagenin (13-0) under the conditions used for the formation of the dihydrosapogenins gives dihydrogitogenin.

The examples are for illustration and can be varied in a good many ways. For instance, acetic anhydride is used as an acylating agent for the alcoholic hydroxyl groups of yuccagenin. How-= C3 into ester or ether or other groups capable of hydrolysis to give hydroxyl. Such agents are, for example, organic acid halides, acetyl chloride, benzoyl chloride, furoyl chloride, butyric anhydride or similar lower fatty acid anhydride, etc. One can also treat yuccagenin with an alkali metal to form an alkali metal alcoholate and 5 then react the latter with an alkyl halide to get an ether of yuccagenin. Triphenylmethyl chloride also reacts with yuccagenin to form a socalled trityl ether. Halides such as sulfuryl chloride, phosphorus chloride and the like can also be used in replacing th OH groups of yuccagenin by groups hydrolyzable to OH. Both hydroxyls can be esterified or etherified and the product then partially hydrolyzed to give one free hydroxyl while the other is in the form of a group hydrolyzable to give OH. Conversely, by carewhere-Yavand- Ya-represent members of the class and ester groups hydrolyzable'to 2. Compounds of formula,

CH: CHr-CH| CH CHI (LIH- and organic carboxylic acid ester groupshydrolyzable to 3. Yuccagenin having the formula on. cHi-cm o. m4. 0H

\fi; H0

H 4. Yuccagenin diacetate having the formula.

ROMEO B. WAGNER. 

